Contraceptive transdermal delivery of hormones

ABSTRACT

Dosing regimen for transdermal delivery of hormones comprising a monthly treatment cycle with a fixed treatment interval and a variable rest interval.

This is a U.S. national filing, pursuant to 35 U.S.C. §371, ofInternational Application

No. PCT/US2009/059826, filed Oct. 7, 2009, which claims benefit of U.S.Provisional Application No. 61/103,741, filed Oct. 8, 2008, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to the field of transdermal delivery, inparticular, of hormones.

BACKGROUND OF THE INVENTION

Progestins, or combinations of progestins and estrogens, are used toinhibit ovulation, and to induce other physiological changes in thefemale reproductive system, and thereby to reduce the risk of pregnancy.

Various dosing regimens have been used to administer such hormones.These include for example, self-administration by oral delivery of aprogestin and an estrogen for 21 days, followed by a 7 day “rest”interval, during which the woman typically experiences withdrawal (i.e.,menstrual) bleeding. Other dosing regimens can also be used, includingdosing regimens that involve longer durations of administration of aprogestin and dosing regimens that involve use of low dose hormoneduring a non-treatment interval.

An important aspect of any effective contraceptive dosing regimen isthat the regimen is convenient so as to facilitate compliance and thatthe doses delivered are effective to prevent or reduce the risk ofpregnancy without exposing the woman to unnecessary risks of sideeffects. Side effects can include hormone-related adverse events andcycle control irregularities, particularly “breakthrough” bleeding.

A transdermal hormone delivery device for administering a progestin andan estrogen via a patch, and a skin permeation enhancer combination foruse therein, are disclosed, e.g., in U.S. Pat. No. 7,045,145 and U.S.20040054901,both of which are incorporated herein by reference as thoughfully set forth.

SUMMARY OF THE INVENTION

The instant invention provides a dosing regimen for administration of aprogestin and, optionally, an estrogen. More specifically, the inventionrelates to a method of preventing pregnancy, i.e., reducing the risk ofpregnancy, in a woman that comprises, during a monthly treatment cyclecomprising a treatment interval and a rest interval,

(A) transdermally administering an effective amount of a progestin and,optionally, an estrogen, during a treatment interval of 3 to 4 weeks and

(B) delivering no hormone or transdermally delivering (i) low doseprogestin, (ii) low dose estrogen, or (iii) low dose progestin and lowdose estrogen during a rest interval that is the balance of the calendarmonth, if any.

In illustrative embodiments, the invention provides a method ofinhibiting conception, i.e., preventing (reducing the risk of)pregnancy, in a woman that comprises, during a monthly treatment cycleconsisting of a treatment interval and a rest interval:

(A) applying a transdermal hormone delivery treatment device to the skinof the woman during the treatment interval, e.g., consecutively applyingmultiple transdermal hormone delivery devices, and

(B) optionally applying a rest interval device during at least a portionof the rest interval, which extends to the end of the calendar month,wherein the rest interval device comprises (i) low dose progestin, (ii)low dose estrogen, (iii) low dose progestin and low dose estrogen, or(iv) no hormone.

In more specific illustrative embodiments, the invention provides amethod of inhibiting conception in a woman that comprises consecutivelyapplying, during a monthly treatment cycle:

-   -   eight transdermal hormone delivery treatment devices to the skin        of the woman during a 28 day treatment interval, each device        being applied for ½ week, and each device comprising an        effective amount of a combination of an estrogen and a        progestin, followed by the rest interval that extends through        the balance of the calendar month, if any, or    -   seven transdermal hormone delivery treatment devices to the skin        of the woman during a 3-½ week treatment interval, each device        being applied for ½ week, and each device comprising an        effective amount of a combination of an estrogen and a        progestin, followed by the rest interval that extends through        the balance of the calendar month, or    -   six transdermal hormone delivery treatment devices to the skin        of the woman during a 3 week treatment interval, each device        being applied for ½ week, and each device comprising an        effective amount of a combination of an estrogen and a        progestin, followed by the rest interval that extends through        the balance of the calendar month, or four transdermal hormone        delivery treatment devices to the skin of the woman during a 28        day treatment interval, each device being applied for 7 days,        and each device comprising an effective amount of an estrogen        and a progestin, followed by the rest interval that extends        through the balance of the calendar month, if any, or    -   three transdermal hormone delivery treatment devices to the skin        of the woman during a 21 day treatment interval, each device        being applied for 7 days, and each device comprising an        effective amount of an estrogen and a progestin, followed by the        rest interval that extends through the balance of the calendar        month.

If a treatment interval is only 3 weeks, such that the rest intervalwould exceed about 7 days, particularly if the rest interval wouldexceed 8 days or would exceed 9 days, then a rest interval devicecomprising low dose hormone would typically be used during all or atleast a portion of the rest interval, as illustrated, e.g., by FIG. 1 d.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates hormone serum concentrations during and after asingle treatment cycle comprising a treatment interval of 21 or 24-½days with or without a hormone containing patch in the rest interval.The figures have been drawn to 31 days for illustrative purposes onlyand do not illustrate hormone serum concentrations during a succeedingtreatment cycle. FIG. 1 a illustrates EE serum concentration levels over31 days resulting from administration of 7 patches each for 3-½ days.FIG. 1 b illustrates EE serum concentration levels over 31 daysresulting from administration of 7 patches each for 3-½ days, followedby administration of a rest interval device (½ patch) for 3-½ days. FIG.1 c illustrates EE serum concentration levels over 31 days resultingfrom administration of 3 patches each for 7 days. FIG. 1 d illustratesEE serum concentration levels over 31 days resulting from administrationof 3 patches each for 7 days, followed by administration of a restinterval device (½ patch) for 7 days.

FIG. 2 illustrates an exploded cross-section of an illustrative dermaldelivery system of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with illustrative embodiments of the present invention,during a monthly treatment cycle, in a single treatment interval,multiple, e.g., six, seven, or eight transdermal hormone deliverydevices, i.e., “patches,” are consecutively applied to the skin of awoman to administer a progestin and, optionally, an estrogen to prevent,i.e., reduce the risk of, pregnancy following sexual intercourse. Inillustrative embodiments of the invention, each patch is intended to beworn for ½ week, i.e., for 3 to 4 days, e.g., 3-½ days. Thus, the totaltreatment interval is

-   -   (a) 6 multiplied by ½ week, i.e., 3 weeks,    -   (b) 7 multiplied by ½ week, i.e., 3-½ weeks, or    -   (c) 8 multiplied by ½ week, i.e., 4 weeks.

Each ½ week period is about 3 to about 4 days. For example, a single½-week device can be worn for 2-½ or 3 days of a given week, in whichcase the other ½-week device would be worn for 4-½ or 4 days of thatweek, respectively, or each device can be worn for 3-½ days each.

In accordance with another illustrative embodiment of the invention,during a monthly treatment cycle, in a single treatment interval, threeor four transdermal hormone delivery devices, i.e., “patches,” areemployed to administer a progestin and, optionally, an estrogen to awoman to prevent pregnancy. Each patch is intended to be worn for 1week. Thus, the total treatment interval is 3 multiplied by 1 week,i.e., 3 weeks, or 4 multiplied by 1 week, i.e., 4 weeks. A one weekdevice can similarly be worn for 6, 6-½, 7-½, and 8 days, although it ispreferable to fix one day per week such that a week is 7 days.

In accordance with another illustrative embodiment of the presentinvention, during a monthly treatment cycle, in a single treatmentinterval, four transdermal hormone delivery devices, i.e., “patches,”are employed to administer a progestin and, optionally, an estrogen to awoman to prevent conception. Three of the patches are intended to beworn for 1 week each, while the remaining patch is worn for ½ week.Thus, the total treatment interval is 3 multiplied by 1 week, i.e., 3weeks, plus 1 multiplied by ½ week, i.e., ½ week, which equals 3-½weeks.

In any event, at the end of each treatment interval, there follows arest interval made up of the days remaining in a given month, if any.So, for example, if the treatment interval is 28 days, as in the case of4 devices each worn for one week or eight devices each worn for one-halfweek, and if the treatment interval begins January 1, March 1, May 1,July 1, August 1, October 1, or December 1, then the total treatmentcycle is 31 days, including a rest interval of 3 days; if the treatmentinterval begins April 1, June 1, September or November 1, then the totaltreatment cycle is 30 days, including a rest interval of two days; ifthe treatment interval begins February 1 in a non-leap year, then thetotal treatment cycle is 28 days, including a rest interval of 0 days;if the treatment interval begins February 1 in a leap year, then thetotal treatment cycle is 29 days, including a rest interval of 1 day.

Treatment cycles can be repeated successively for as long as desired.This invention contemplates that a woman will generally undergo at least2 successive treatment cycles before interrupting or alteringcontraceptive treatment. For example, a woman can undergo 3, 4, 5, 6, ormore successive treatment periods. In a typical contraceptive program, awoman will follow such regimen for at least one calendar year.

Treatment intervals need not begin on the first day of a calendar month,but should each begin on a fixed day each month. So, for example, if thetreatment interval is 28 days, and if the treatment interval beginsJanuary 10, then the last treatment device would be removed on February7 and the rest interval would comprise February 7, 8, and 9, and thenext treatment cycle would being on February. 10.

A woman may choose to begin wearing the first patch of the firsttreatment interval on, or about on, the first day of the woman's period,i.e., on the first day of menstrual bleeding. In this case, the womancan employ a longer or shorter initial treatment interval or initialrest interval, in order to get her on to a schedule that is convenientfor her. So, for example, if a woman begins her period on a June 15 andapplies the first treatment device that evening, options available toher include, among others:

(i) going directly to a 28 day treatment interval by consecutivelywearing treatment devices for 28 days, i.e., until the evening of July13, and then having a rest interval until resuming another 28 daytreatment interval on July 15;

(ii) consecutively wearing treatment devices until close to the end ofthe month, e.g., June 25, 26, 27, 28 or 29, and then having a restinterval until starting a new 28 day treatment interval on July 1;

(iii) consecutively wearing treatment devices until July 24, 25, 26, 27,28, 29, or 30, and then having a rest interval until starting a 28 daytreatment interval on August 1.

In some embodiments of the invention, there is a minimum treatmentinterval of 21 days prior to the first rest interval. If the minimumtreatment interval is 21 days, then option (ii) in the illustrativeexample above, would not be available. In any event, after the initial“phase-in” time interval, a 21 to 28 day treatment interval is typicallyemployed, e.g., 21, 24-½, or 28 days.

An illustrative regimen for use of seven ½-week devices, starting withapplication of a first treatment device on the evening of Sunday, Feb.1, 2009, is illustrated graphically in the following table showing acalendar for February, March, and April, 2009. In these tables, patchesare indicated by the superscript or subscript numbers 1 through 7, withsuperscript values indicating application in the morning and thesubscript values indicating application in the evening. “RI” indicatesthe start of the rest interval.

Illustrative Seven 3½ Day Patches Regimen Sun Mon Tues Weds Thurs FriSat Treatment Cycle 1 - February 2009  1₁  2  3  4   5²  6  7  8₃  9 1011  12⁴ 13 14 15₅ 16 17 18  19⁶ 20 21 22₇ 23 24 25   26^(RI) 27 28Treatment Cycle 2 - March 2009  1₁  2  3  4   5²  6  7  8₃  9 10 11  12⁴13 14 15₅ 16 17 18  19⁶ 10 21 22₇ 23 24 25   26^(RI) 27 28 29  30 31Treatment Cycle 3 - April 2009  1₁  2   3  4  5²  6  7  8₃  9  10 11 12⁴13 14 15₅ 16  17 18 19⁶ 20 21 22₇ 23  24 25  26^(RI) 27 28 29  30 

In an alternative embodiment of the invention, a user applies six 3-½day patches during a treatment interval of 21 days, followed by a restinterval, as illustrated below.

Illustrative Six 3½ Day Patches Regimen Sun Mon Tues Weds Thurs Fri SatTreatment Cycle 1 - February 2009  1₁  2  3  4   5²  6  7  8₃  9 10 11 12⁴ 13 14 15₅ 16 17 18  19⁶ 20 21  22_(RI) 23 24 25  26  27 28 TreatmentCycle 2 - March 2009  1₁  2  3  4   5²  6  7  8₃  9 10 11  12⁴ 13 14 15₅16 17 18  19⁶ 10 21  22_(RI) 23 24 25  26  27 28 29  30 31 TreatmentCycle 3 - April 2009  1₁  2   3  4  5²  6  7  8₃  9  10 11 12⁴ 13 14 15₅16  17 18 19⁶ 20 21  22_(RI) 23  24 25 26  27 28 29  30 

Such regimen results in a rest interval of more than 7 days. Typically,a rest interval would not exceed 7 days. If a regimen is chosen thatprovides such extended rest interval, it may be advantageous toadminister low dose hormone during all or a portion of such restinterval. By “low dose” is meant a dose that is not effective forcontraception if used throughout a treatment interval.

In another illustrative embodiment of the invention, a user applies four7-day patches during a treatment interval of 28 days followed by a restinterval (if there are any days remaining in the calendar month).

Illustrative Four 7-Day Patches Regimen Sun Mon Tues Weds Thurs Fri SatTreatment Cycle 1 - February 2009  1₁  2  3  4   5  6  7  8₂  9 10 11 12 13 14 15₃ 16 17 18  19 20 21 22₄ 23 24 25  26 27 28 Treatment Cycle2 - March 2009  1₁  2  3  4   5  6  7  8₂  9 10 11  12 13 14 15₃ 16 1718  19 10 21 22₄ 23 24 25  26 27 28  29_(RI) 30 31 Treatment Cycle 3 -April 2009  1₁  2  3  4  5   6  7  8₂  9 10 11 12  13 14 15₃ 16 17 1819  20 21 22₄ 23 24 25 26  27 28  29_(RI) 30

It will be appreciated that in each of the above illustrations, thefirst day of each treatment cycle, i.e., the first day of application ofa new device, is designated as Day 1. It could have been designated Day0 (as in FIG. 1, discussed below) in which case, all other day numberswould be reduced by one. It will further be appreciated that the firstapplication in this illustration is made on the afternoon/evening of Day1, shown here as a Sunday, but that the first application can also bemade on a Sunday morning or in the morning, afternoon, or evening of anyother day of the week.

It should also be appreciated that while the above illustrations use 3-½days as a ½ week interval, it is also possible in accordance with thisinvention to wear one patch for 2-½ to 4-½ days, e.g., 3-4 days perweek, and another patch for the balance of the week, so long as twosuccessive ½ week periods total seven or about seven days. Preferably,at least one day per week is fixed, e.g., each Sunday either a newdevice is applied or a rest interval begins. This is illustrated in thefollowing table for eight ½-Week patches.

Illustrative Eight ½-Week Patches Regimen Sun Mon Tues Weds Thurs FriSat Treatment Cycle 1 - February 2009  1₁  2  3  4  5²  6  7  8³  9 10 11₄ 12  13 14 15₅ 16 17 18 19₆ 20 21 22₇ 23 24  25⁸ 26  27 28 TreatmentCycle 2 - March 2009  1₁  2  3  4²  5  6  7  8₃  9 10 11   12₄ 13 14 15⁵16 17 18₆ 19 20 21 22₇ 23 24 25⁸ 26 27 28  29_(RI) 30 31 Treatment Cycle3 - April 2009  1₁  2  3  4  5₂  6  7  8₃  9 10 11 12₄ 13 14 15   16₅ 1718 19₆ 20 21 22  23  24⁷ 25 26⁸ 27 28  29_(RI) 30

In other embodiments, each ½ week is fixed at 3-½ days.

In embodiments of the invention, only a progestin is administered duringtreatment intervals. In other embodiments, the progestin is administeredin combination with an estrogen during treatment intervals, for all or aportion of each treatment interval. In either case, a progestin or anestrogen or both can but is not necessarily administered during all or aportion of the rest interval, as described below.

The amount of hormone in each treatment device, e.g., each 3-½ day patchor 7 day patch, can be varied from patch to patch, or week to week, toprovide a multiphasic treatment regimen. For example, the amounts ofhormone can be varied so as to provide a triphasic delivery regimen suchas, e.g., the triphasic oral contraceptive disclosed in U.S. Pat. No.6,214,815 (Ortho-McNeil). Either or both of the progestin and theestrogen can be varied (or maintained) independently of each other.Alternatively, the amount of the progestin and of the estrogen can bethe same in all patches used in a given treatment cycle or in alltreatment cycles.

It is desirable that each treatment device result in an averageprogestin serum concentration level equivalent to at least about 750pg/ml of levonorgestrel during the entire treatment interval. In someembodiments, the average progestin serum concentration level isequivalent to at least about 500 pg/ml of levonorgestrel during week 1of the treatment interval and/or is at least about 750 pg/ml during week2 and week 3 of each treatment interval, it being understood, however,that such levels may not be achieved during the entire first treatmentcycle. In particular, for example, such levels may not be achievedduring the first week of the first treatment cycle.

In addition, serum concentrations of a progestin, as well as of anestrogen, can vary from patient to patient. Thus, when consideringaverage serum concentrations achieved during treatment intervals, it isuseful to refer to a population of subjects, e.g., 10 or more, 25 ormore, 50 or more, 75 or more, or 100 or more. Thus, the concentrationvalues, and peak-trough relationships, expressed herein may be achievedin a population of subjects but not necessarily in every subject withina given population.

The amount of estrogen delivered during each treatment interval can bean amount that results in serum concentration levels equivalent to about5 to about 80, e.g., about 15 to about 65, pg/ml of ethinyl estradiolduring the entire treatment interval, or about 20 to about 30 pg/ml.Serum concentration levels that average about 20 to about 30 pg/mlethinyl estradiol equivalent can be achieved during week 2 and week 3 ofeach treatment interval.

In an illustrative embodiment of the invention, low (or lower) dosehormone(s) can be delivered during all or a part of the rest interval.The amount of hormone delivered during the rest interval is no more thanabout 80%, e.g., about 20% to about 80%, of the amount delivered duringthe treatment interval. For example, the amount of hormone(s) deliveredduring the rest interval can be about ¾, about ⅔, about ½, about ⅓, orabout ¼ of the amount delivered during an equivalent amount of timeduring the treatment interval. Such amount may attenuate, i.e., lessenthe severity of, symptoms of menstruation, which can include excessivevaginal bleeding, mood changes, headaches, dysmenorrhea and othersymptoms associated with hormone withdrawal, especially sudden hormonewithdrawal, or otherwise.

Such rest interval patch, or rest interval device, can conveniently bemade in the same manner as the treatment device but with a reducedamount of hormone(s). The amount of hormone(s) can be reduced, forexample, by reducing the size of the patch. For example, if a treatmentpatch has a surface area of 20 cm² and it is desired to deliver 50% ofthe hormones during the rest interval, then the rest interval device canbe the same as the treatment interval device but reduced in size to havea surface area of 10 cm². Such rest interval device could be referred toas a “half patch.” Similarly, one could administer a “quarter patch” todeliver 25% of the hormones, or a patch of any other fraction of thesize of the treatment patch. Alternatively, the size (surface area) ofthe rest interval device can be the same as the size of the treatmentdevice, in which case it would be loaded with reduced amounts ofhormones and/or enhancers.

The rest interval device can be worn for any part or the whole of therest interval. So, for example, a half patch can be worn for the fullrest interval.

FIG. 1 shows illustrative hormone serum concentration levels over 31days. In accordance with the practice of this invention, of course, afresh device would be applied sooner during months with 28, 29, or 30days.

As illustrated in FIG. 1, patches can be designed so as to delivervarying amounts of hormone(s) during the period of wear of each patch,such that there is a peak serum concentration level that occurs afterthe patch is applied and a trough serum concentration level that occursat the time the patch is removed. This characteristic can be usefullyemployed to deliver an amount of a progestin or an estrogen, or both,during the rest interval that declines as the end of the rest intervalapproaches such that the amount of hormone delivered by the end of therest interval is decreased relative to peak levels during wear of therest interval device and, in some embodiments, relative to serumconcentration levels on the day that the rest interval device isapplied. Such device can be referred to as a descending dose device.

Use of such rest interval device can have several advantages. In oneembodiment, the rest interval device is a placebo and is used as amatter of convenience, e.g., so that the woman stays in the habit ofremoving and applying a patch every 3-12 days or every 7 days. Inanother embodiment, low dose hormone is delivered such that the womanexperiences menstruation but with attenuated symptoms. In suchembodiment, also, hormone serum concentration levels are adjustedgradually rather than “all or nothing”.

A 3-½ day patch can be smaller than a 7 day patch therefore making itless noticeable to the wearer and persons around her. The adhesivenessrequirements are also eased because the patch is smaller and because itdoesn't need to stay attached for a full week. If a 3-½ day patch doesbecome dislodged, there will only be a short period of time before thenext patch is due to be applied. A 3-½ day patch can allow for apharmacokinetic (PK) profile having peaks and troughs during each wearperiod, i.e., during each 3-½ day period of treatment, but such peaksand troughs can be smoother relative to a 7 day patch. So, for example,peak hormone serum concentrations during the period of time in which asingle treatment device (other than the first device) is worn can be atleast about 1.1 times trough levels, or at least about 1.25 times thetrough levels, but also can be no more than about twice the troughlevels, or no more than about 1.8 times the trough levels, or no morethan about 1.5 times the trough levels. FIG. 1 illustrates suchpeak-trough PK profiles. Such PK profile can be achieved during anentire treatment interval or during at least a single wear interval,e.g., the third week, the second half of the second or third weeks, orat least 2 weeks, e.g., the second and third weeks, of each treatmentinterval.

Any transdermal hormone delivery device that delivers a progestin and,optionally, an estrogen, in amounts effective to effect contraception,i.e., to prevent pregnancy, can be used in the practice of theinvention. “Preventing pregnancy” does not necessarily mean that suchdevices are 100% effective in preventing pregnancy in all cases but suchdevices can have, at least, approximately the same contraceptiveefficacy as currently available oral contraceptives. A transdermalhormone delivery device for preventing pregnancy that delivers17-deacetyl norgestimate and ethinyl estradiol is disclosed in U.S. Pat.No. 5,876,746 (Cygnus) and is marketed as Ortho Evra(r)(norelgestromin/ethinyl estradiol transdermal system). As shown in theprescribing information, Ortho Evra provides a more or less “flat”delivery, i.e., no or only a slight peak-trough PK profile for eachperiod of wear of a single patch.

The invention also comprises a kit comprising multiple patches eachintended to be worn for ½ week (2-½ to 4-½ days) or 1 week (6-8 days).For example, such kit may comprise seven ½ week treatment devices, orsome multiple of 7, e.g., 14, 21, 28, 35, or 42 treatment devices. Or,for example, such kit may comprise six ½ week treatment devices, or somemultiple of 6, e.g., 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, or 72treatment devices. Or, for example, such kit may comprise three 7 daytreatment devices, or some multiple of 3, e.g., 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, or 36 treatment devices. Each kit can also comprise amix of ½ week and one week devices. For example, a kit may comprisethree 7 day treatment devices, or some multiple of 3, e.g., 3, 6, 9, 12,15, 18, 21, 24, 27, 30, 33, or 36 treatment devices, and one ½ weektreatment device for every three one week devices. In each case, the kitwould include instructions for use of the devices in accordance with themethod of the invention.

Such kit can also comprise rest interval devices, which can be placebos(i.e., no hormone) or low dose hormone devices, as discussed above. Forexample, a kit for a seven patches/treatment cycle regimen can compriseforty-two ½ week treatment devices and six rest interval devices; a kitfor a six patches/ treatment cycle regimen can comprise seventy-two ½week treatment device and twelve rest interval devices; a kit for a 3patches/ treatment cycle regimen can comprise nine 7 day treatmentdevices and three rest interval devices; etc.

Such rest interval devices can be clearly indicated as rest intervaldevices, directly or on individual patch packaging, such as by size,color, shape, or markings, to avoid confusion with treatment devices. Ifa multiphasic hormone delivery profile is desired, then each treatmentdevice can be marked, directly or on individual patch packaging, tominimize the risk that a user will apply patches out of order.

FIG. 1 illustrates projected serum concentration levels of ethinylestradiol (EE) resulting from administration of patches such asdescribed in U.S. Pat. No. 7,045,145 and U.S. 20040054901 andhereinbelow.

The data in FIG. 1 are illustrative and do not show the effect ofapplying a new patch on Day 29. The data are projections calculated onthe basis of actual human cadaver skin flux data obtained using a deviceloaded with a polymeric matrix comprising LNG and EE, substantially asdescribed below, and having a skin contact area of approximately 9.4cm². The projections are calculated using an approximate in vivoclearance rate for EE. FIGS. 1 a and 1 b show EE levels on each of Days1 through 28, with a first 3-½ day patch being applied on Day 0 andsubsequent patches being applied on Days 4, 7, 11, 14, 18, and 21. FIGS.1 c and 1 d show EE levels on each of Days 1 through 28, with a first 7day patch being applied on Day 0 and subsequent patches being applied onDays 7 and 14. FIGS. 1 b and 1 d show the effects of administering arest interval patch on Days 24-28, said rest interval device being ½ thesize of, but otherwise identical to, the treatment patch.

A similar pattern of peaks/troughs can be obtained with progestins,e.g., LNG.

Note that because these data are projected from skin flux data, actualresults will vary, depending, e.g., upon the skin surface area of thepatch employed, the concentration of hormone(s), and the efficacy of theskin permeation enhancer.

An illustrative device that can be used in the practice of the instantinvention is illustrated in FIG. 2.

With reference to FIG. 2, this illustrative device comprises 4 layers.One is the AI layer (6). The second is a release liner (4). The third isan internal backing layer (5). The fourth is an overlay, which in thisillustrative device, itself comprises three component layers (1, 2, 3),referred to herein below as, respectively, a PSA layer (3), anintermediate layer (2), and an overlay covering or overlay coating (1).The overlay can also be described as comprising a PSA layer (3) and anoverlay covering (1, 2). In any event, a feature of this device isformation of a seal between the PSA layer (3) of the overlay (1, 2, 3)and the release liner (4).

The AI layer

Layer 6 comprises the AI and carriers comprising skin permeationenhancers, a humectant/plasticizer, and a PSA matrix. The AI comprise aprogestin, e.g., levonorgestrel, and an estrogen, e.g., ethinylestradiol or 17-β estradiol.

Skin Permeation Enhancers: A combination of skin permeation enhancingagents is employed that comprises a mixture of (1) a pharmaceuticallyacceptable organic solvent, such as dimethyl sulfoxide (DMSO), (2) afatty (C8-C20) alcohol ester of a hydroxy acid, such as lauryl lactate,(3) a lower (C1-C4) alkyl ester of a hydroxy acid, e.g., ethyl lactate,and (4) a C6-C18 fatty acid, such as capric acid. In specificembodiments, the fatty alcohol ester of lactic acid is lauryl lactateand the lower alkyl ester of lactic acid is ethyl lactate. A medium- tolong-chain fatty acid in the skin permeation enhancer formulation can beemployed among the skin permeation enhancers. Capric acid has been usedbut other C6-C 18 saturated or unsaturated fatty acids include but arenot limited to caproic acid, caprytic acid, lauric acid and myristicacid.

In a particular such embodiment, the pharmaceutically acceptable organicsolvent is DMSO. Other organic solvents include but are not limited toC1-C8 branched or unbranched alcohols, such as ethanol, propanol,isopropanol, butanol, isobutanol, and the like, as well as azone(laurocapram: 1-dodecylhexahydro-2H-azepin-2-one) andmethylsulfonylmethane.

The fatty alcohol ester of a hydroxy acid can be a fatty alcohol esterof lactic acid, such as lauryl lactate. However, other hydroxy acids andfatty alcohols may be utilized. Alternative hydroxy acids include butare not limited to alpha-hydroxy acids such as glycolic acid, tartaricacid, citric acid, malic acid and mandelic acid, as well as thebeta-hydroxy acid, salicylic acid. Alternative fatty alcohols includeany C8-C20 saturated or unsaturated fatty alcohols, such as myristyl,palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid can also utilize lactic acid, andcan be, e.g., ethyl lactate. However, other hydroxy acids, such asglycolic acid, tartaric acid, citric acid, malic acid, mandelic acid andsalicylic acid, may also be utilized. In addition isopropylmyristic acid(IPM) may be used as a substitute for the lower alkyl ester of hydroxyacid.

Hormones: LNG is a potent progestin on a weight-dose basis, which is animportant factor since progestins often exhibit a much lesser degree oftransdermal absorption than do estrogens. Other progestins that could beused in part or total are norgestrel, norgestimate, desogestrel,gestodene, norethindrone, nore-thynodrel, hydrogesterone, ethynodioldicetate, hydroxyprogesterone caproate, medroxyprogesterone acetate,norethindrone acetate, progesterone, megestrol acetate, gestogen andcertain others which are biocompatible and absorbable transdermally.These include biocompatible derivatives of progestins that aretransdermally absorbed, some of which, advantageously, arebioconvertible after transdermal absorption to the original progestin.The progestin and other hormones selected preferably have highcompatibility with each other.

For combinations of progestin with estrogen, the synthetic hormone EE isparticularly suitable, although natural estrogen or other analogs can beused. This hormone may be transdermally delivered in conjunction withthe particularly suitable progestin, levonorgestrel, at desirable dailyrates for both hormones. EE and LNG are compatible and can be dispersedin the adhesive polymer formulation.

Derivatives of 17β-estradiol that are biocompatible, capable of beingabsorbed transdermally and preferably bioconvertible to 17β-estradiolmay also be used, if the amount of absorption meets the required dailydose of the estrogen component and if the hormone components arecompatible. Such derivatives of estradiol include esters, either mono-or di-esters. The monoesters can be either 3- or 17-esters. Theestradiol esters can be, illustratively speaking, estradiol-3,17-diacetate; estradiol-3-acetate; estradiol 17-acetate; estradiol-3,17- divalerate; estradiol-3-valerate; estradiol-17-valerate; 3-mono-,17-mono- and 3,17-dipivilate esters; 3-mono-, 17-mono- and3,17-dipropionate esters; 3-mono-, 17-mono- and 3,17-dicyclopentyl-propionate esters; corresponding cypionate, heptanoate, benzoateand the like esters; ethinyl estradiol; estrone; and other estrogenicsteroids and derivatives thereof that are transdermally absorbable.

Combinations of the above with estradiol itself (for example, acombination of estradiol and estradiol-17-valerate or further acombination of estradiol-17-valerate and estradiol-3, 17-divalerate) canbe used with beneficial results. For example, 15-80% of each compoundbased on the total weight of the estrogenic steroid component can beused to obtain the desired result. Other combinations can also be usedto obtain desired absorption and levels of 17β-estradiol in the body ofthe subject being treated.

It will be appreciated that the hormones may be employed not only in theform of the pure chemical compounds, but also in a mixture with otherpharmaceuticals that may be transdermally applied or with otheringredients which are not incompatible with the desired objective aslisted above. Thus, simple pharmacologically, acceptable derivatives ofthe hormones such as ethers, esters, amides, acetals, salts and thelike, if appropriate, may be used. In some cases, such derivatives maybe preferred. The progestin compound and the estrogenic steroid areordinarily dispersed or dissolved concurrently in fabricating thehormone-containing adhesive polymer matrix or they may be dispersed ordissolved separately.

Polymers Used as Active Patch Components: The AI-containing layer can bea polymer matrix comprising the pharmaceutically or cosmetically activeingredient. The polymer can be a PSA to form a biologically acceptableadhesive polymer matrix, preferably capable of forming thin films orcoatings through which the AI can pass at a controlled rate. Suitablepolymers are biologically and pharmaceutically compatible,nonallergenic, insoluble in and compatible with body fluids or tissueswith which the device is contacted. The use of water soluble polymers isgenerally less preferred since dissolution or erosion of the matrixwould affect the release rate of the AI as well as the capability of thedosage unit to remain in place on the skin. So, in certain embodiments,the polymer is non-water soluble.

Preferably, polymers used to form a polymer matrix in the AI-containinglayer have glass transition temperatures below room temperature. Thepolymers are preferably non-crystalline but may have some crystallinityif necessary for the development of other desired properties.Cross-linking monomeric units or sites can be incorporated into suchpolymers. For example, cross-linking monomers that can be incorporatedinto polyacrylate polymers include polymethacrylic esters of polyolssuch as butylene diacrylate and dimethacrylate, trimethylol propanetrimethacrylate and the like. Other monomers that provide such sitesinclude allyl acrylate, allyl methacrylate, diallyl maleate and thelike.

In certain transdermal drug delivery devices, there is a a permeable orrupturable barrier, rate controlling membrane, or the like interposedbetween the AI-containing material and the release liner such that whenthe release liner is removed, said barrier remains in place. The purposeof such barrier can be, e.g., to prevent the AI-containing material fromflowing out of the device or to control the rate of absorption by theskin. In the device used to generate the data illustrated in FIG. 1,there is no need for a layer between the release liner and the AI layerbecause the polymer matrix is adhered to the remaining layers of thedevice and does not readily flow and because the matrix is designed todeliver adequate drug across the skin without a need to restrict theflow rate. Thus, the polymer matrix is adhered directly to the releaseliner and, upon administration to the skin, the polymer matrix isadhered directly to the skin across the entire surface area of the AIlayer exposed by removal of the release liner.

A useful adhesive polymer formulation comprises a polyacrylate adhesivepolymer of the general formula (I):

wherein “X” represents the number of repeating units sufficient toprovide the desired properties in the adhesive polymer and R is H or alower (C1-C10) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyland the like. More specifically, it is preferred that the adhesivepolymer matrix comprises a polyacrylate adhesive copolymer having a2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinylacetate as a co-monomer. An example of a suitable polyacrylate adhesivecopolymer for use in the present invention includes, but is not limitedto, that sold under the tradename of Duro Tak 87-4098 by National Starchand Chemical Co., Bridgewater, N.J., which comprises a certainpercentage of vinyl acetate co-monomer.

Humectant/plasticizer: Preferably, a plasticizer/humectant is dispersedwithin the adhesive polymer formulation. Incorporation of a humectant inthe formulation allows the dosage unit to absorb moisture from thesurface of skin which in turn helps to reduce skin irritation and toprevent the adhesive polymer matrix of the delivery system from failing.The plasticizer/humectant may be a conventional plasticizer used in thepharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). Inparticular, PVP/vinyl acetate (PVP/VA) co-polymers, such as those havinga molecular weight of from about 50,000, are suitable for use in thepresent invention. The PVP/VA acts as both a plasticizer, acting tocontrol the rigidity of the polymer matrix, as well as a humectant,acting to regulate moisture content of the matrix. The PVP/VA can be,for example, PVP/VA S-630 which is a 60:40 PVP:VA co-polymer that has amolecular weight of 51,000 and a glass transition temperature of 110 C.The amount of humectant/plasticizer is directly related to the durationof adhesion of the overlay. The PVP/vinyl acetate can be PVP/VA S-630supplied by International Specialty Products, Inc. (ISP) of Wayne, N.J.,wherein the PVP and the vinyl acetate are each present in approximatelyequal weight percent.

The shape of the device of the invention is not critical. For example,it can be circular, i.e., a disc, or it can be polygonal, e.g.,rectangular, or elliptical. The surface area of the AI layer generallyshould not exceed about 60 cm² in area. Preferably, it will be about 5to 50 cm², more preferably, about 8 to about 40 cm². Most preferably,the discs will be about 10 to about 20 cm². A disc of 15 cm² may bepreferred because it is relatively small but can be capable ofdispersing high levels of hormones.

Thus, an illustrative hormone-comprising polymer matrix useful fordelivering an effective amount of a progestin and of an estrogen inamounts effective to prevent pregnancy in accordance with the method ofthe invention comprises a polyacrylate adhesive copolymer with about 3%to about 60% w/w vinyl acetate and, on a weight percentage basis of theadhesive polymer matrix:

-   -   a) from about 15% to about 35% of PVP/VA;    -   b) from about 10% to about 30% percent of a combination of skin        permeation enhancing agents which is a mixture comprising from        about 4% to about 12% DMSO, from about 4.2% to about 12.6%        lauryl lactate, from about 0.7% to about 2.3% ethyl lactate, and        from about 3% to about 9% capric acid; and    -   c) from about _(—)0.6% to about 1.2% LNG and EE, e.g., about        0.87% LNG and about 0.77% EE.        The Internal Backing Layer

An internal backing layer can be made of any suitable material that isimpermeable or substantially impermeable to the AI and to excipients ofthe adhesive polymer matrix. The internal backing layer serves as aprotective cover for the AI layer and provides a support function. Thebacking layer can be formed so that it is essentially the same size asthe hormone-containing adhesive polymer matrix or it can be of largerdimension so that it can extend beyond the edges of the AI-containingpatch outwardly. The backing layer can be any appropriate thickness thatwill provide the desired protective and support functions. A suitablethickness is from about 10 to about 300 microns. More specifically, thethickness is less than about 150 microns, yet more specifically, it isless than about 100 microns, and most specifically, the thickness isless than about 50 microns.

Examples of materials suitable for making the internal backing layer arefilms of polypropylene, polyesters such as poly(ethylene terephthalate),metal foils, metal foil laminates of such suitable polymer films, andthe like. Polyester films, such as Mylar® (DuPont Teijin) and Scotchpak®9732 (3M Company), are particularly suitable for use in the presentinvention.

The Release Liner

The surface area of the release liner is greater than that of the AIlayer. This can be seen in FIG. 3, where the diameter (in the case of around device) or width and length (in the case of a polygonal device) ofLayer 3 is greater than that of Layers 5 and 6, such that it extendsbeyond the AI layer in some or all directions.

The release liner is made of any material (1) that is impermeable orsubstantially impermeable to the components of the AI layer, (2) towhich the PSA in the overlay will adhere, as discussed furtherhereinbelow, and (3) that is readily removable by peeling from the AIlayer and overlay PSA just prior to applying to the skin.

The release liner can have the same dimensions as the overlay, discussedbelow, or it can extend totally or partially beyond the edge of thepatch. In one embodiment, the release liner extends partially beyond theoverlay so as to form “tabs” of release liner material that extendbeyond the edges of the overlay for easy separation of the release linerfrom the rest of the system.

It can comprise a fluorinated or siliconized polyester film or anotherfluorinated or siliconized polymer such as a polyacrylonitrilecopolymer, or a foil lined with a siliconized or fluorinated polymer.The release liner is preferably not polystyrene because it has beenshown that polystyrene will absorb DMSO. A preferred material for therelease liner when the layer 4 a of the overlay comprises a PIB PSA is aScotchpak® liner (3M Company), such as Scotchpak® 1022 or Scotchpak®9744 fluorinated polyester release liners.

The Overlay

The overlay comprises a PSA in which the solubility of the volatilecomponents is less, preferably significantly less, than the solubilityof those same components in the AI matrix. So, e.g., when the volatilecomponent is DMSO or ethyl lactate, a PIB PSA may be chosen. Withreference to FIG. 2, the PIB PSA layer is Layer 3. Generally, such PIBPSA comprises a mix of a low to medium molecular weight and a highmolecular weight PIB, a plasticizer such as polybutene, and ahydrocolloid such as a cross-linked polyvinylpyrrolidine. Useful PIBsinclude, e.g., Oppanol® PIBs (BASF), which have average molecularweights of between 40,000 and 4,000,000.

A useful PIB PSA comprises crospovidone such as Kollidon® CLMcrospovidone (BASF) (e.g., 5-45 wt %, preferably 15-30 wt %, and morepreferably 20-25 wt %); a low viscosity PIB such as Oppanol® B12(molecular weight: 51000, viscosity at 150 C: 150 Pascal-seconds) (e.g.,10-60 wt %, preferably 30-50 wt %); a high viscosity PIB such asOppanol® B100 (viscosity: approximately 1100 Pascal-seconds) (e.g., 2-15wt %, preferably 5-15 wt %); a polybutene such as Indopol® 1900(Innovene LLC) (molecular weight: 2500, viscosity at 100 C: 3900-4200centistokes) (e.g., 10-60 wt %, preferably 20-40 wt %); and a mineraloil (0-20 wt %). For example, an illustrative formulation comprisesabout 20 wt % crospovidone, about 40 wt % of a low viscosity PIB, about8 wt % of a high viscosity PIB and about 32 wt % of polybutene. (Theterm, “about,” as used in this specification, means plus or minus 10%.By “low viscosity” is meant less than about 300 Pascal-seconds and by“high viscosity” is meant more than about 800 Pascal-seconds, when theviscosity is measured at 150 C.) Cross-linking of the PVP is usefulbecause such cross-linked polymers tend to be water-swellable but waterinsoluble. Such PIB PSA can provide good wear stability, e.g.,attachment under normal living conditions for at least 7 days.

Other rubber-based polymers that can be used in place of PIB PSA in theoverlay include silicone-based PSAs, such as BIO-PSA® (Dow Corning);copolymers and terpolymers of styrene/butadiene/styrene,styrene/isoprene/styrene, and styrene-ethylene/butylenes-styrene, suchas Kraton D styrene/butadiene and Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styrene.Isoprene rubbers, such as Kraton IR linear polyisoprene homopolymers,can also be used.

As shown in FIG. 2, and like the release liner, the overlay can extendbeyond the perimeter of the AI layer in all directions, typically by amargin of about 0.1 to about 1.5 cm, more specifically about 0.3 toabout 1.2 cm, and yet more specifically about 0.8 cm beyond theperimeter of the AI layer.

The overlay, if it comprises a PSA layer, improves adherence to the skinby supplementing the adhesion provided by the PSA in the AI layer, ifpresent, or, in the case of an AI layer that does not comprise a PSA, itprovides adherence to the skin.

In addition, the overlay adheres to the release liner around theperimeter of both layers, thereby sealing in the components of the AIlayer. By properly selecting the materials that comprise the overlay andthe release liner, this seal between them prevents, or substantiallyprevents, escape of the volatile component in the AI layer but stillallows the release liner to be peeled away easily by the user prior totopical application.

The seal is formed in situ by mechanically pressing together the edgesof the overlay that extend beyond the perimeter of the AI layer and theedges of the release liner that extend beyond the perimeter of the AIlayer. When the first overlay layer is a PIB PSA and the release lineris a fluorinated or siliconized polyester film, a suitable seal can bemade by applying pressure. The amount of pressure required to form suchseal is not critical. Finger pressure is adequate. Of course, in anillustrative embodiment of the invention, it is desirable that the sealcan be broken by peeling the release liner from the rest of the systemby hand just prior to application to the skin.

The seal between the overlay PSA and the release liner prevents, orsubstantially prevents, loss of the components of the AI layer throughthe seal between these two layers such as during storage of the system.The seal is preferably “tight” to the internal backing layer and the AIlayer such that there is minimal or no seepage of the polymer matrixinto spaces between the overlay and the release liner or between theoverlay and the internal backing layer or the Al layer.

The overlay can also comprise a covering (1) that does not comprise aPSA, i.e., that comprises a non-PSA layer, such that the surface of theoverlay that is exposed to fingers, clothing and ambient dirt or dust isnon-tacky, is flexible or malleable so as to flex with skin and musclemovements, is of an unnoticeable or attractive color and texture, andpermits moisture from the skin to pass through the device owing to itsbeing porous or otherwise permeable to water.

Thus, it may be desirable to utilize a multi-layered overlay comprisinga first layer of a PSA in which the volatile component is insoluble,covered with an intermediate layer and an overlay covering having theproperties described above. Such illustrative overlay is illustrated inFIG. 2 as Layers 1, 2, and 3.

While a PIB PSA is useful for containing DMSO or ethyl lactate, or both,in the AI layer, the PIB PSA may flow through most overlay coveringshaving the properties described above. Such flow of the PIB PSA cancause the device to become tacky and discolored. Therefore, it may bedesirable to use an overlay covering that itself comprises two layers,one of which is a polymeric layer interposed between the PIB PSA (anintermediate layer) and a backing layer. Such intermediate layer can bea polyacrylate PSA as described above, because such PSA willsubstantially prevent flow of the PIB PSA into and through the overlaycovering but will substantially not itself migrate into or through theoverlay covering.

The overlay is a laminate that comprises three layers: a PIB PSA layer(3, in FIG. 2); an intermediate layer that comprises a material thatdoes not permit flow of the PIB PSA but that does permit passage ofmoisture (2, in FIG. 2); and an overlay covering (or backing layer) thatis non-tacky, attractive, flexible, and moisture permeable (1, in FIG.2).

Materials useful in the intermediate layer include, e.g., polyacrylates,polyurethanes, plasticized polyvinyl chlorides, and copolymers ofpolyethylene and ethyl vinyl acetate. Rubber-based polymers that are ofvery high molecular weight, e.g., at least about 150,000 Daltons canalso be used, as can rubber-based polymers that can be crosslinked.Examples include the Kraton D styrene/butadiene, Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styreneand Kraton IR linear polyisoprene homopolymers Butyl rubbers andsilicone rubbers, which are cross-linkable, can also be used. Theintermediate layer can comprise a PSA that binds the first overlay layeras well as the overlay covering. High molecular weight, cross-linkedpolymers are preferred. Preferably, such PSA is a polyacrylate such asis described above with reference to the AI layer.

Materials used in the overlay covering are not PSAs. They include, forexample, a polyurethane film, foam or spun bonded structure, apolyolefin foam, a PVC foam or a woven or non-woven fabric. Illustrativewovens include KOB 051, 053 and 055 woven polyesters (Karl Otto Braun.)Illustrative non-woven fabrics include polyesters. An illustrativepolyurethane material is CoTran^(TM) 9700 melt-blown polyurethanenonwoven backing (3M), which can be colored in skin tones. Suitablematerials are described, e.g., as backing layers in U.S. Pat. No.6,660,295.

If the overlay covering is not porous, then it can be used without anintermediate layer. However, if the overlay covering is not porous,adhesion problems can result from a build up of moisture in the skin/PIBPSA interface. Use of a solid material, i.e., one that is not porous,but that is otherwise permeable to water, such as a thin, e.g., 1 mil(i.e., 0.001 inch), polyurethane film, can be used. However, a porousmaterial such as a foam or fabric will, in general, better retain itsshape and provide good adhesion.

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification withinthe scope of the appended claims. Published patent applications andpatents referenced in this specification are incorporated herein byreference as though fully set forth.

The invention claimed is:
 1. A method of preventing pregnancy in a womanthat comprises, during a treatment cycle based on a calendar month: (A)transdermally administering a contraceptively effective amount of aprogestin and an estrogen during a three-week treatment interval bysuccessive applications of transdermal hormone delivery devices; and (B)transdermally administering low dose progestin and low dose estrogenthroughout rest interval that is the balance of the calendar month byapplication of a transermal hormone delivery device, wherein theprogestin is levonorgestrel; the amount of the progestin deliveredduring the treatment interval results in an average levonorgestrel serumconcentration of at least 750 pg/ml; the amount of the progestindelivered during the rest interval results in an average levonorgestrelserum concentration that is 25% to 75% the amount of the progestindelivered during the treatment interval; the estrogen is ethinylestradiol; the amount of the estrogen delivered during the treatmentinterval results in an average ethinyl estradiol serum concentration ofat least 15pg/ml; and the amount of the estrogen delivered during therest interval results in an average ethinyl estradiol serumconcentration that is 25% to 75% the amount of the estrogen deliveredduring the treatment interval; whereby the woman experiencesmenstruation with attenuated symptoms of menstruation during the restinterval.
 2. The method of claim 1, comprising: (A) transdermallyadministering the contraceptively effective amounts of the progestin andthe estrogen during the treatment interval by successive weeklyapplications of three transdermal hormone delivery devices, one for eachweek of each treatment interval; and (B) transdermally administering thelow dose progestin and low dose estrogen throughout the rest interval byapplication of a transdermal hormone delivery device during the restinterval.
 3. The method of claim 2, wherein each device worn during thetreatment interval provides a peak serum hormone concentration levelafter the patch is applied and a trough serum concentration level at thetime the patch is removed, the peak levels being at least about 1.25times trough levels.
 4. The method of claim 2, wherein the rest intervaldevice has the same hormone concentrations as the treatment intervaldevice but is a fraction of the size of the treatment interval device.5. The method of claim 2, wherein the rest interval device is the samesize as the treatment interval device but comprises reduced hormoneamounts compared to the treatment interval device.
 6. The method ofclaim 2, wherein: (a) the amount of levonorgestrel delivered during therest interval is ¼, ⅓, ½, 2/3 or 3/4 of the amount delivered from eachtreatment interval device during the treatment interval; and (b) theamount of ethinyl estradiol delivered during the rest interval is ¼, ⅓,½, 2/3 or 3/4 of the amount delivered from each treatment intervaldevice during the treatment interval.
 7. The method of claim 6, whereinthe rest interval device is worn during all of the rest interval.